Ultrasensitivity in signaling cascades revisited: Linking local and global ultrasensitivity estimations

ALEJANDRA VENTURA; ALEJANDRO COLMAN-LERNER; ALEJANDRO COLMAN-LERNER; ARIEL CHERNOMORETZ; EDGAR ALTSZYLER; ARIEL CHERNOMORETZ; EDGAR ALTSZYLER; ALEJANDRA VENTURA

PLOS ONE

PUBLIC LIBRARY SCIENCE

Lugar: San Francisco; Año: 2017

1932-6203

Ultrasensitive response motifs, capable of converting graded stimuli into binary responses, are well-conserved in signal transduction networks. Although it has been shown that a cascade arrangement of multiple ultrasensitive modules can enhance the system?s ultrasensitivity, how a given combination of layers affects a cascade?s ultrasensitivity remains an open question for the general case. Here, we introduce a methodology that allows us to determine the presence of sequestration effects and to quantify the relative contribution of each module to the overall cascade?s ultrasensitivity. The proposed analysis framework provides a natural link between global and local ultrasensitivity descriptors and it is particularly well-suited to characterize and understand mathematical models used to study real biological systems. As a case study, we have considered three mathematical models introduced by O?Shaughnessy et al. to study a tunable synthetic MAPK cascade, and we show how our methodology can help modelers better understand alternative models.